A model for receptor–peptide binding at the glucagon‐like peptide‐1 (GLP‐1) receptor through the analysis of truncated ligands and receptors
S Al‐Sabah, D Donnelly - British journal of pharmacology, 2003 - Wiley Online Library
S Al‐Sabah, D Donnelly
British journal of pharmacology, 2003•Wiley Online LibraryThe receptor for glucagon‐like peptide‐1 (GLP‐1) can be activated by both its physiological
hormone and a peptide discovered in the venom of the Gila Monster, exendin‐4, which
shows promise as an antidiabetic agent. Exendin‐4 displays receptor‐binding properties not
observed for GLP‐1. Firstly, exendin‐4 can be truncated by up to eight residues at its N‐
terminus without a significant loss of affinity. Secondly, exendin‐4 maintains high affinity for
the isolated N‐terminal domain of the receptor, suggesting that exendin‐4 makes additional …
hormone and a peptide discovered in the venom of the Gila Monster, exendin‐4, which
shows promise as an antidiabetic agent. Exendin‐4 displays receptor‐binding properties not
observed for GLP‐1. Firstly, exendin‐4 can be truncated by up to eight residues at its N‐
terminus without a significant loss of affinity. Secondly, exendin‐4 maintains high affinity for
the isolated N‐terminal domain of the receptor, suggesting that exendin‐4 makes additional …
- The receptor for glucagon‐like peptide‐1 (GLP‐1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin‐4, which shows promise as an antidiabetic agent.
- Exendin‐4 displays receptor‐binding properties not observed for GLP‐1. Firstly, exendin‐4 can be truncated by up to eight residues at its N‐terminus without a significant loss of affinity. Secondly, exendin‐4 maintains high affinity for the isolated N‐terminal domain of the receptor, suggesting that exendin‐4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand–receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain.
- In order to further understand the nature of the receptor–peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin‐4 and GLP‐1 to receptor affinity.
- Our data show that, for both exendin‐4 and GLP‐1, the primary interaction is between the putative helical region of the peptide and the extracellular N‐terminal domain of the receptor.
- However, we demonstrate that the contribution to receptor affinity provided by the N‐terminal segment of GLP‐1 is greater than that of exendin‐4, while the C‐terminal nine residue extension of exendin‐4, absent in GLP‐1, forms a compensatory interaction with the N‐terminal domain of the receptor.
- We describe a peptide–receptor binding model to account for these data.
British Journal of Pharmacology (2003) 140, 339–346. doi:10.1038/sj.bjp.0705453
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